EP1008602B1 - Pulverisierte-Sorbitol und ihr Verfahren zur Herstellung - Google Patents

Pulverisierte-Sorbitol und ihr Verfahren zur Herstellung Download PDF

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Publication number
EP1008602B1
EP1008602B1 EP99403095A EP99403095A EP1008602B1 EP 1008602 B1 EP1008602 B1 EP 1008602B1 EP 99403095 A EP99403095 A EP 99403095A EP 99403095 A EP99403095 A EP 99403095A EP 1008602 B1 EP1008602 B1 EP 1008602B1
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Prior art keywords
sorbitol
pulverulent
test
exhibits
powder
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EP99403095A
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English (en)
French (fr)
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EP1008602B8 (de
EP1008602A1 (de
EP1008602B2 (de
Inventor
Franck Moraly
Erik Labergerie
José Lis
Philippe Lefevre
Frédéric Bouvier
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Roquette Freres SA
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Roquette Freres SA
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H3/00—Compounds containing only hydrogen atoms and saccharide radicals having only carbon, hydrogen, and oxygen atoms
    • C07H3/04—Disaccharides
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23G—COCOA; COCOA PRODUCTS, e.g. CHOCOLATE; SUBSTITUTES FOR COCOA OR COCOA PRODUCTS; CONFECTIONERY; CHEWING GUM; ICE-CREAM; PREPARATION THEREOF
    • A23G3/00—Sweetmeats; Confectionery; Marzipan; Coated or filled products
    • A23G3/34—Sweetmeats, confectionery or marzipan; Processes for the preparation thereof
    • A23G3/346—Finished or semi-finished products in the form of powders, paste or liquids
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L27/00—Spices; Flavouring agents or condiments; Artificial sweetening agents; Table salts; Dietetic salt substitutes; Preparation or treatment thereof
    • A23L27/30—Artificial sweetening agents
    • A23L27/33—Artificial sweetening agents containing sugars or derivatives
    • A23L27/34—Sugar alcohols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C31/00—Saturated compounds having hydroxy or O-metal groups bound to acyclic carbon atoms
    • C07C31/18—Polyhydroxylic acyclic alcohols
    • C07C31/26—Hexahydroxylic alcohols
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H3/00—Compounds containing only hydrogen atoms and saccharide radicals having only carbon, hydrogen, and oxygen atoms
    • C07H3/06—Oligosaccharides, i.e. having three to five saccharide radicals attached to each other by glycosidic linkages

Definitions

  • the present invention relates to a sorbitol powder of low hygroscopicity and surface high specificity, with a low density, a particular particle size and an excellent flowability.
  • the invention also relates to a sorbitol powder whose technical properties of use in direct compression are improved, as well as a process for its preparation.
  • Sorbitol is a predominantly used hexitol in the areas of food applications and as a sweetening agent, but also for its reduced caloricity and acariogenicity.
  • Sorbitol powder just like the others pulverulent polyols such as xylitol or mannitol, is as for him of current use like excipient as a sweetener and a texturizing agent food industry, and as an additive support in all types of industries. It is however better excipient than xylitol and mannitol, especially in compression, because of its special ability to crystallize in the form of crystals into needles, directly compressible.
  • the patent application FR 2 622 190 describes a sorbitol powder containing particles of a diameter. average between 300 and 500 microns.
  • the high bulk density and the relatively low specific surface area of said particles are not significantly modified by the manufacturing method used, so that the pulverulent sorbitol thus obtained retains the same moisture absorption factor and solubility in water as the starting sorbitol powder.
  • EP 32 288 discloses a ⁇ -sorbitol polymorph of disintegrated and loose crystalline structure, having improved hygroscopicity and satisfactory compression properties. However, these particular properties relate only to a grain size cut of between 250 and 841 ⁇ m (ie 20/60 mesh), the specific surface area of which is in any case less than 2 m 2 / g.
  • its hygroscopicity determined according to the test A is between 0.5 and 1.6%, preferably between 0.9 and 1.4%.
  • Test A is to establish the isotherm curve of water sorption at 20 ° C expressing the percentage of resumption of water of a pulverulent product dehydrated that one places in an atmosphere of content in variable relative humidity and at a temperature of 20 ° C. Determination of the hygroscopicity of the product powder will then be the percentage of water recovery, at 60% relative humidity at equilibrium (or 60% E.R.H. for Equilibrium Relative Humidity).
  • the specific surface area is determined on the whole the particle size distribution of sorbitol powder thanks to a specific surface analyzer Quantachrome based on a nitrogen absorption test on the surface of the product under analysis, following the technique described in the article BET Surface Area by Nitrogen Absorption of S. BRUNAUER et al. (Journal of American Chemical Society, 60, 309, 1938).
  • a pulverulent sorbitol may jointly have a specific surface area of at least 2 m 2 / g, preferably at least 2.2 m 2 / g and a hygroscopicity of less than 2%, preferably less than 2 m 2 / g. 1.7%. Indeed, it is very classically accepted that the hygroscopicity of a powdery product increases with its specific surface, ie its surface exposed to the medium containing water vapor.
  • the pulverulent sorbitol according to the invention has a high specific surface, characteristic of a granulated product, yet with a low hygroscopicity, characteristic of a crystallized product in a stable crystalline form.
  • the sorbitol marketed by MERCK under the name SORBITOL grade L has a hygroscopicity of 2.4% to 60% of ERH according to test A, for a BET specific surface of 1.55. m 2 / g, and the sorbitol marketed by the applicant under the trademark NEOSORB® P 60 W, has a hygroscopicity, under the same conditions of measurement, a value of 1.53% for a specific surface area of less than 1 m 2 / g.
  • the powdery sorbitol compliant to the invention has a hygroscopicity remarkably weaker than what is conventionally described for commercial sorbitol powder with surfaces highest specific.
  • sorbitol powder according to the invention has much better properties, especially as support additive, a standard powdery sorbitol. These are due, at least in part, to the specific area particularly high of this product.
  • the Applicant Company considers as novel a powdery sorbitol characterized in that it has a BET specific surface area of greater than 2.5 m 2 / g, preferably of between 2.6 and 4 m 2 / g, and more preferably still between 2.6 and 3.5 m 2 / g.
  • the pulverulent sorbitol according to the invention can also be characterized by its apparent density, properties in direct compression and its friability.
  • the determination of the apparent density is achieved through the use of a commercialized device by the company HOSOKAWA under the brand POWDER TESTER in applying the recommended method to measure a apparent density.
  • the powdered sorbitol according to the invention has an apparent density low, ie between 0.35 and 0.65 g / ml, preferably between 0.4 and 0.6 g / ml.
  • the compressibility of powdered sorbitol is determined according to the following test B, described in the patent EP 220.103 of which the Applicant Company holds.
  • This test B consists in measuring the force, expressed in Newton, which is representative of the compressibility of sorbitol powdery studied. This force therefore reflects the crush strength of a tablet that is cylindrical with convex sides (radius of curvature 14 mm), with a diameter of 13 mm, a thickness of 6 mm and weighing 0.647 g, being a density apparent 1.1 g / ml.
  • the compressibility of the powdery sorbitol compliant to the invention is determined at a value usually between 100 and 150 N, more particularly at a value between 120 and 140 N.
  • This test C consists in subjecting 15 g of sorbitol powder to be tested, having a particle size between 100 and 200 ⁇ m, for 15 minutes, at the mechanical action of an ERWEKA TAP friabilimeter of the company HERWEKA (6056 Heusenstamm - DE), in rotation to a uniform speed of 25 rpm, in which 5 identical steel balls with a diameter of 17 mm and a weight of 18.87 g were introduced, the friability according to this test being the percentage by weight of powder not retained after the test on a sieve with a width of mesh of 100 ⁇ m.
  • the friability of the powdered sorbitol conforms to the invention presents a value generally between 10 and 50%, preferably between 20 and 40%.
  • the resistance mechanical tablets obtained with said sorbitol powder is indeed particularly high, compared to tablets obtained with commercial products.
  • the qualities of sorbitol powder marketed by the company DHW RODLEBEN, with a density of 0.6 g / ml exhibit a compressibility, determined according to test B, close to 100 N.
  • the low density of powdery sorbitol compliant to the invention and its character of mechanical resistance high allow to advantageously reduce the material implemented for the manufacture of tablets or tablets, thereby significantly reducing the production costs.
  • the pulverulent sorbitol according to the invention check the rule that the higher the density apparent amount of a powdered sorbitol is low, the higher its friability is high.
  • the sorbitol powder according to the invention generally a mean diameter of between 150 and 250 ⁇ m, and a particle size distribution between 60 and 500 ⁇ m. These values are determined on a Laser LS granulometer COULTER® brand.
  • the pulverulent sorbitol according to the invention has an excellent flow note, usually at least 70, preferably between 70 and 90, and more preferably between 70 and 80. This value is slightly higher than those of the powders of sorbitol of the prior art obtained by granulation. This is all the more remarkable as compared to these products, pulverulent sorbitol according to the invention has a finer grain size.
  • the sorbitol powder according to the invention is relatively pure, that is to say that it presents a high sorbitol richness, generally greater than 95% and more particularly greater than 98% by weight.
  • sorbitol powdery The powdered sorbitol complies with the invention is then easily differentiated from a sorbitol powder obtained by simple atomization, composed of essentially spherical particles, or sorbitol obtained by extrusion, comprising particles angular shaped lumps of thin oriented needles in the same direction.
  • the pulverulent sorbitol according to the invention is likely to be obtained by proceeding to a stage of granulation of a sorbitol powder by wet using binder, and then to a maturing stage by drying the granulated sorbitol thus obtained.
  • a sorbitol powder according to the invention having the stated functional characteristics, the company Applicant has found that it is appropriate to choose sorbitol starting sorbitol powder, which can be obtained by coating, spraying, extrusion or by crystallization in water or in another solvent like alcohol.
  • the particle size of said sorbitol starting powder is not in itself a factor limiting to produce a powdery sorbitol consistent with the invention.
  • the binder consists of water or a sorbitol syrup of a dry matter not exceeding 100%, preferably between 10 and 80%.
  • a continuous mixer-granulator type Vertical FLEXOMIX marketed by the company HOSOKAWA SCHUGI, or horizontal CB type marketed by the L ⁇ DIGE company in which, via a dosing device, weight, the starting sorbitol powder to be granulated in continuous and via a volumetric doser, the binder (water or the sorbitol solution) continuously.
  • Granulation can also be done in a spray tower, or in a fluidized bed granulator.
  • a mixer-granulator FLEXOMIX vertical type HOSOKAWA SCHUGI In a first preferred embodiment of the process for the preparation of a powdery sorbitol to the invention, it is chosen to use a mixer-granulator FLEXOMIX vertical type HOSOKAWA SCHUGI.
  • the starting sorbitol powder and the binder are very intimately mixed in the mixer-granulator equipped with an axis with knives arranged in blades, and a nozzles liquid spray system injection.
  • the good dispersion of constituents and the agglomeration of particles of the starting sorbitol powder are performed by high speed stirring, i.e. value at least equal to 1500 rpm, preferably at least equal to 3000 rpm.
  • the granules formed are discharged continuously on a dryer. Unloading is preferably done by gravity in the case of said vertical granulator, and by thrust, via the axis of the rotary knives, if the horizontal granulator is used.
  • This second stage of drying out of the mixer-granulator allows the removal of water from binder and to crystallize the dry matter from the binder, in the case where a sorbitol solution has been in such a way that crystallisation takes place produce after the previous granulation step.
  • the dryer can be for example a fluidized bed dryer or a rotary maturing drum.
  • Powdery sorbitol according to the invention is obtained after cooling and possibly sieving. In this case, the fines particles can be directly recycled at the head of granulation, and the larger particles are crushed and recycled at the top of sieving or granulation head.
  • MSD atomization tower Multi-Stage Dryer
  • water evaporation capacity the order of 350 kg / h with sorbitol powder at a rate between 400 and 600 kg / h, the granulation being with water as a binder, as will be exemplified hereinafter.
  • the pulverulent sorbitol according to the invention can advantageously be used, because of the quality of its functional properties mentioned above, in the application "tablets to suck”.
  • Tablets prepared from said sorbitol indeed present, in addition to a high compressibility which results in a high hardness for a weak density, a smooth texture in the mouth.
  • This last organoleptic property is particularly appreciated for the manufacture of tablets or tablets because a "rasping" character for tablets is considered a non-hedonistic character by specialists in this domain.
  • a FLEXOMIX mixer-granulator is fed SCHUGI continuously via a powder dispenser, at a flow rate of 500 kg / h, with a sorbitol powder manufactured by coating.
  • the mixer-granulator feeds the mixer-granulator continuously with water at 60 ° C and a flow rate of 40 l / h, via a spray nozzle.
  • the rotating knife axis is preset at a speed of 3000 rpm.
  • the wet granulated powder at the mixer-granulator outlet falls continuously, by gravity, into a bed dryer fluidized SCHUGI with two compartments.
  • the granulated product is dried with air at 120 ° C and then cooled by air at 20 ° C in the second compartment.
  • the granulated, dried and cooled product is then screened continuously on a rotary screen equipped with two 120 and 600 ⁇ m metal screens.
  • the starting powder sorbitol A and the powdery sorbitol B thus obtained in accordance with the invention have the characteristics shown in the following Table I.
  • a FLEXOMIX mixer-granulator is fed SCHUGI continuously via a powder dispenser, with the sorbitol starting powder A, and under the same conditions than in Example 1, but said mixer-granulator is fed with a 70% sorbitol solution of dry matter as a binder, at a flow rate of 40 l / h and a temperature of 60 ° C via a spray nozzle.
  • the pulverulent sorbitol C and D according to the invention obtained respectively with a heating air temperature of 120 ° C. and 75 ° C., have the characteristics shown in the following Table II.
  • Settings C D Sorbitol richness (% by weight) 98.5 98.5 Water content (%) 0.45 0.55 Melting temperature (according to DSC; ° C) 98.9 99.2 Heat of fusion (according to DSC, J / g) 172 175 Hygroscopicity (% to 60% ERH) 1.2 1.4 Specific surface (m 2 / g) 2.75 2.2 Apparent density (g / ml) 0.47 0.42 Average diameter ( ⁇ m) 192 193 Flow note (value / 100) 75 74 Compressibility (N) 120 130 Friability (%) 25 22
  • the process is carried out in the same manner as in Example 1, but with a sorbitol starting powder of finer granulometry.
  • the starting powder sorbitol E and the powdery sorbitol F according to the invention have the characteristics shown in the following Table III.
  • the process is carried out with the same sorbitol starting powder E which has been used in the example 3.
  • An MSD atomizing tower of 350 kg / h capacity evaporation is fed with sorbitol powder E to reason of 410 kg / h.
  • the granulation with water is carried out by spraying water at a rate of 80 l / h through a nozzle at 45 bar pressure.
  • the drying air is at 136 ° C. and is discharged at 78 ° C. the temperature of the steam is determined at 142 ° C, the bed static down the tower being cooled by air to 70 ° C.
  • the product passes on a vibrated fluid bed where it is cooled by air in 3 temperature zones respectively fixed at 35 ° C, 20 ° C and 20 ° C.
  • Product G has the characteristics summarized in the following Table IV: Settings E F Sorbitol content (% by weight) 98 98 Water content (%) 0.5 0.25 Melting temperature (according to DSC; ° C) 97.5 99 Heat of fusion (according to DSC, J / g) 168 169 Hygroscopicity (% to 60% ERH) 1.9 1 Specific surface area (m / g) 0.9 3.25 Apparent density (g / ml) 0.5 0.47 Average diameter ( ⁇ m) 60 300 Flow note (value 100) 60 80 Compressibility (N) 65 135 Friability nd 30
  • Powdery sorbitols according to the invention all possess, contrary to the products of art prior art, excellent functional properties, making them suitable for use without inconvenience as excipients and carriers of non-hygroscopic additives, in particularly in the food and pharmaceutical.
  • sorbitol for each powdery sorbitol, in this case here a sorbitol marketed by MERCK under the name SORBITOL grade L, and a sorbitol according to the invention prepared according to Example 1, a series of convex tablets, 13 mm in diameter, obtained on alternative press FROGERAIS AM, after extemporaneous mixture with 0.7% magnesium stearate.
  • tablets made with sorbitol powder according to the invention differ from tablets made with the other sorbitol, by the fact that they simultaneously exhibit compressibility high (high hardness for low density) and smooth texture in the mouth.

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Claims (11)

  1. Pulverförmiger Sorbit, dadurch gekennzeichnet, daß er folgende Daten aufweist:
    einen in einem Test A bestimmten Hygroskopizitätswert unter 2%, vorzugsweise unter 1,7%, wobei der Test A darin besteht, daß die Wassersorptions-Isotherme bei 20°C erstellt wird, die den Prozentsatz der Wasseraufnahme eines zuvor dehydratisierten pulverförmigen Produkts ausdrückt, das man in eine Atmosphäre mit veränderlichem Gehalt an relativer Feuchtigkeit und mit einer Temperatur von 20°C bringt, wobei die Bestimmung der Hygroskopizität des pulverförmigen Produkts hierbei der Prozentsatz der Wasseraufnahme bei 60% relativer Feuchtigkeit im Gleichgewicht ( oder 60% E.R.H. für Equilibrium Relative Humidity) ist,
    eine nach der Methode BET bestimmte spezifische Oberfläche von mindestens gleich 2 m2/g, vorzugsweise mindestens gleich 2,2 m2/g.
  2. Pulverförmiger Sorbit, dadurch gekennzeichnet, daß er eine spezifische Oberfläche nach der Methode BET von über 2,5, vorzugsweise zwischen 2,6 und 4 m2/g und noch bevorzugter zwischen 2,6 und 3,5 m2/g aufweist.
  3. Pulverförmiger Sorbit nach einem der Ansprüche 1 und 2, dadurch gekennzeichnet, daß er einen Hygroskopizitätswert zwischen 0,5 und 1,6 %, vorzugsweise zwischen 0,9 und 1,4 %, aufweist.
  4. Pulverförmiger Sorbit nach einem der Ansprüche 1 bis 3, dadurch gekennzeichnet, daß er folgende Daten aufweist:
    eine nach der Methode HOSOKAWA bestimmte scheinbare Dichte zwischen 0,35 und 0,65 g/ml, vorzugsweise zwischen 0,4 und 0,6 g/ml,
    eine in einem Test B bestimmte Komprimierbarkeit zwischen 100 und 150 N und insbesondere zwischen 120 und 140 N, wobei der Test B darin besteht, daß man die in Newton ausgedrückte Kraft mißt, die ein Ausdruck für die Komprimierbarkeit des untersuchten pulverförmigen Sorbits ist, wobei diese Kraft hier also die Druckfestigkeit einer zylindrischen Tablette mit konvexen Seiten (Krümmungsradius 14 mm) mit einem Durchmesser von 13 mm, einer Dicke von 6 mm und einem Gewicht von 0,647 g, d.h. einer scheinbaren Volumenmasse von 1,1 g/ml, darstellt,
    eine in einem Test C bestimmte Mürbheit zwischen 10 und 50 %, vorzugsweise zwischen 20 und 40 %.
  5. Pulverförmiger Sorbit nach einem der Ansprüche 1 bis 4, dadurch gekennzeichnet, daß er folgende Daten aufweist:
    einen mittleren Durchmesser zwischen 150 und 250 µm,
    eine Fließzahl von mindestens 70, vorzugsweise zwischen 70 und 90 und noch bevorzugter zwischen 70 und 80.
  6. Pulverförmiger Sorbit nach einem der Ansprüche 1 bis 5, dadurch gekennzeichnet, daß er folgende Daten aufweist:
    einen Gehalt an Sorbit über 95 %, vorzugsweise über 98 %,
    einen Schmelzpunkt zwischen 98 und 99,5 °C, vorzugsweise zwischen 98,9 und 99,2 °C,
    einen Kristallaufbau, bei dem reichliche dünne Nadeln von Sorbit γ ohne besondere Ausrichtung sich an der Oberfläche von Teilchen mit veränderlichen Formen befinden, denen Zonen mit mehr geschmolzenem Aussehen zugeordnet sind.
  7. Verfahren zur Herstellung von pulverförmigem Sorbit nach einem der Ansprüche 1 bis 6, dadurch gekennzeichnet, daß es die Schritte der nassen Granulierung von pulverförmigem Sorbit mit Hilfe eines Bindemittels und einen Schritt der Reifung des auf diese Weise erhaltenen granulierten Sorbits durch Trocknung umfaßt.
  8. Herstellungsverfahren nach Anspruch 7, dadurch gekennzeichnet, daß der Schritt der Granulierung in einer kontinuierlichen Misch- und Granuliervorrichtung durchgeführt wird.
  9. Herstellungsverfahren nach Anspruch 7, dadurch gekennzeichnet, daß der Schritt der Granulierung in einem Zerstäubungsturm durchgeführt wird.
  10. Verwendung von pulverförmigem Sorbit nach einem der Ansprüche 1 bis 6 als Süßungsmittel, Texturmittel, Zusatzträger oder -grundlage in insbesondere für den Nahrungsmittel- und pharmazeutischen Bereich bestimmten Zusammensetzungen.
  11. Verwendung von pulverförmigem Sorbit nach einem der Ansprüche 1 bis 6, für die Herstellung von Tabletten, die in einem Test D, der darin besteht, daß eine Reihe von konvexen Tabletten mit einem Durchmesser von 13 mm hergestellt werden, die auf einer sich hin- und herbewegenden Presse FROGERAIS AM nach Direktmischung mit 0,7 % Magnesiumstearat erhalten wurden, eine glatte Textur im Mund, d.h. keine Wahrnehmung eines rauhen Charakters, aufweisen.
EP99403095.5A 1998-12-11 1999-12-09 Pulverisierte-Sorbitol und ihr Verfahren zur Herstellung Expired - Lifetime EP1008602B8 (de)

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DE69907119.4T DE69907119T3 (de) 1998-12-11 1999-12-09 Pulverisierte-Sorbitol und ihr Verfahren zur Herstellung

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FR9815681 1998-12-11
FR9815681A FR2787110B1 (fr) 1998-12-11 1998-12-11 Sorbitol pulverulent et son procede de preparation

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EP1008602A1 EP1008602A1 (de) 2000-06-14
EP1008602B1 true EP1008602B1 (de) 2003-04-23
EP1008602B2 EP1008602B2 (de) 2018-11-21
EP1008602B8 EP1008602B8 (de) 2019-02-27

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US (3) US6274778B1 (de)
EP (1) EP1008602B8 (de)
JP (1) JP2000175653A (de)
KR (1) KR100788520B1 (de)
CN (1) CN1141282C (de)
AT (1) ATE238323T1 (de)
BR (1) BR9905826A (de)
CA (1) CA2290805C (de)
DE (1) DE69907119T3 (de)
DK (1) DK1008602T3 (de)
ES (1) ES2196743T5 (de)
FR (1) FR2787110B1 (de)
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US6358060B2 (en) * 1998-09-03 2002-03-19 Jsr Llc Two-stage transmucosal medicine delivery system for symptom relief
US20020098264A1 (en) * 1998-11-27 2002-07-25 Cherukuri Subraman R. Medicated chewing gum delivery system for nicotine
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FR2787110B1 (fr) 2001-02-16
DK1008602T3 (da) 2003-08-11
EP1008602B8 (de) 2019-02-27
CA2290805A1 (fr) 2000-06-11
CN1259508A (zh) 2000-07-12
ES2196743T3 (es) 2003-12-16
US6274778B1 (en) 2001-08-14
PT1008602E (pt) 2003-09-30
ID24667A (id) 2000-07-27
KR20000062194A (ko) 2000-10-25
ES2196743T5 (es) 2019-03-21
DE69907119T2 (de) 2004-02-05
ATE238323T1 (de) 2003-05-15
EP1008602A1 (de) 2000-06-14
DE69907119T3 (de) 2019-06-13
CA2290805C (fr) 2010-05-25
US6365789B2 (en) 2002-04-02
EP1008602B2 (de) 2018-11-21
DE69907119D1 (de) 2003-05-28
CN1141282C (zh) 2004-03-10
US6387402B1 (en) 2002-05-14
BR9905826A (pt) 2000-08-08
FR2787110A1 (fr) 2000-06-16
KR100788520B1 (ko) 2007-12-24
JP2000175653A (ja) 2000-06-27
US20020016518A1 (en) 2002-02-07

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